Coenzyme Q10 (CoQ10) or ubiquinone, a redox component of the mitochondrial electron transport chains, is a powerful antioxidant and membrane stabilizer that may prevent cellular damage during myocardial ischemia and reperfusion therapy. Coenzyme Q10 has been used primarily as an adjuvant therapy for some cardiomyopathies. However, one of the main problems in CoQ10 administration is the high variability of endogenous plasma and tissue levels, which seems to be dependent on several factors. This work explores temporal 24h and seasonal variation as well as gender and racial differences in endogenous plasma ubiquinone concentration. Coenzyme Q10 measurements (quantified by HPLC-UV) of 16 healthy volunteers were done during the daytime hours of activity beginning at 09:00h one day and ending at 09:00h the next day (13 different determinations) in two distinct months. April and October, of the year. A statistically significant circadian rhythm in plasma ubiquinone concentration that includes only the fundamental 24h component was demonstrated both in the April and October data. Furthermore, the time-point means of the ubiquinone concentration in the October study were invariably higher than those obtained in the April study. No statistically significant differences were found in CoQ10 concentration between male and female subjects, both in April and in October. In addition, racial differences were demonstrated; lower plasma ubiquinone levels were found in Caucasian compared to African subjects. However, the latter small group of subjects failed to demonstrate a circadian rhythm, neither in the April nor in the October analysis.

The therapeutic use of the immunosuppressive agent cyclosporin A (CsA) is associated with arterial hypertension and increased risk of thromboembolism. Impaired endothelium-mediated relaxation is one of the main hypotheses explaining the CsA-induced vascular hyper-reactivity. Since nitric oxide (NO) modulates both vascular and platelet activity, we studied the effects of CsA on the levels of arterial and platelet NO as well as 3',5'-cyclic guanosine monophosphate (cGMP) levels which are influenced by NO. An animal model of CsA-induced hypertension was used. Wistar rats were treated with a clinically relevant, oral dose of 5 mg/kg CsA, daily, for 4 weeks. CsA increased both systolic and diastolic blood pressures compared to non-treated rats (P < 0.01). Nitrite, a NO metabolite, decreased in the entire aorta wall (30%, P < 0.05) and in the aorta wall without the endothelial layer (70 %, P < 0.05) in CsA-treated vs. control groups. cGMP content was also decreased in the CsA-treated group (67%, P < 0.01) vs. control. Taken together, these results suggest a defect on the endothelial NO generation, acceleration of breakdown and/or consumption of NO, as well as marked alterations directly on cGMP metabolism. Conversely, platelet nitrite and cGMP content significantly increased in the CsA-treated rats, which was also observed in in vitro studies of platelet nitrite release following CsA treatment. This suggests a platelet self-regulation mechanism against CsA-induced platelet hyper-reactivity, which, in turn, could compensate vascular impairment.

Increased vascular reactivity associated with cyclosporin A (CsA)-induced arterial hypertension might result from increased vasoconstriction and/or decreased vasodilatation. The administration of organic NO donors could have beneficial effects by the NO-cGMP reposition, but there is the risk of sympathetic nervous system worsening by neuro-hormonal counter-regulation. We evaluate the effect of preventive and regressive (curative) isosorbide 5-mononitrate (Is-5-Mn) treatment on blood pressures and on plasma, platelets, adrenals, left ventricle and aorta norepinephrine (NE) and epinephrine (E) contents, assessed by HPLC, in CsA-induced hypertensive rats. Five rat groups were tested: control (orange juice), CsA (5 mg/kg/day) and Is-5-Mn (150 mg/kg/day, bid) groups were treated for 7 weeks; preventive group (Is-5-Mn + CsA): Is-5-Mn during 2 weeks plus 7 weeks of Is-5-Mn + CsA; regressive group (CsA + Is-5-Mn): CsA during 7 weeks plus 5 weeks of CsA + Is-5-Mn. The increased BP in the CsA group was prevented, but was not reverted, by concomitant Is-5-Mn treatment. In the CsA-treated rats, there was a noticeable decrease in left ventricle NE and E contents and aorta NE levels and a moderate increase in circulating catecholamines, without significant effect in the adrenals values. When Is-5-Mn was preventively used, the CsA-induced effect on left ventricle and aorta was prevented. Concomitantly, however, the plasma-platelet catecholamine balance was disrupted, accumulating NE in plasma, whereas E increased in aorta, mimic the single Is-5-Mn-treated group. In opposition, in the group used as regressive Is-5-Mn therapy, the adrenals contents were higher compared with the CsA-group and, simultaneously, the CsA-evoked effects on circulating, left ventricle and

No abstract

1. The aim of the present study was to evaluate the effect of preventive and curative isosorbide-5-mononitrate (Is-5-Mn) treatment on the development of hypertension, cGMP content, thromboxane (TX) A(2)/prostaglandin (PG) I2 balance, the peripheral serotonergic system, platelet activation, lipid peroxidation and plasma lipids in cyclosporine A (CsA)-induced hypertensive rats. 2. Control, CsA (5 mg/kg per day) and Is-5-Mn (150 mg/kg per day, b.i.d.) rat groups were treated orally over a period of 7 weeks. The preventive Is-5-Mn group (Is-5-Mn + CsA) was first treated for 2 weeks with Is-5-Mn, followed by 7 weeks with both drugs; the curative Is-5-Mn group (CsA + Is-5-Mn) was treated for a period of 7 weeks with CsA and with both drugs for an additional 5 weeks. The control group received oral vehicle. 3. Whereas in the group undergoing preventive treatment the CsA-induced increase in blood pressure (BP), compared with the control group, was avoided, in the group undergoing curative treatment, the increase in BP was even higher. The decreased arterial cGMP content in the CsA group was prevented and reverted when Is-Mn was administered either preventatively or curatively with CsA. Platelet TXA2 production, although unaffected in the Is-5-Mn + CsA group, was significantly higher in the CsA + Is-5-Mn group compared with the group receiving CsA alone. Furthermore, plasma TXA2 was reduced following preventive Is-5-Mn treatment, but was worsened in the group undergoing curative therapy. Aortic PGI2 synthesis was identical in all groups. Consequently, the TXA2/PGI2 ratio was only altered in the CsA + Is-5-Mn group, demonstrating a markedly higher value. In both groups treated simultaneously with CsA and Is-5-Mn, a higher platelet 5-hydroxytryptamine (5-HT) content was obtained compared with CsA treatment alone, but only preventive treatment with Is-5-Mn resulted in a significant reduction in plasma 5-HT. Changes in ADP and collagen-induced platelet aggregation paralleled those of plasma 5-HT and TXA2: the hyperaggregation profile of the CsA group, although partially prevented, was not reverted by simultaneous treatment with Is-5-Mn and CsA. Lipid peroxidation and lipid profile values also worsened in the CsA + Is-5-Mn group compared with the group administered CsA alone. 4. In conclusion, the beneficial effects of concomitant Is-5-Mn and CsA treatment were demonstrated when Is-5-Mn was administered preventatively because not only was arterial hypertension prevented, but platelet aggregation and plasma TXA2 and 5-HT levels were also reduced. In contrast, following curative treatment, the BP, platelet/vascular vasoconstrictor balance, lipid peroxidation and plasma lipids were aggravated, recommending a judicious evaluation of the impact of nitrate therapy throughout the period of its administration.